The present invention relates to substituted N-acylsulfonamides which are useful for promoting apoptosis, methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
Apoptosis is a mode of cell death in which the cell commits suicide either to ensure proper development of the organism or to destroy cells that represent a threat to the organism""s integrity. Morphologically, apoptosis is characterized by blebbing of the plasma membrane, shrinking of the cytoplasm and nucleus, and fragmenting into particles which are engulfed by phagocytic cells. Although apoptosis plays a critical role in normal development, its impairment is thought to be a significant factor in the etiology of such diseases as cancer, autoimmune disorders, inflammatory diseases, and viral infections. Conversely, increased apoptosis has been linked to AIDS and neurodegenerative diseases such as Parkinson""s disease, stroke, and Alzheimer""s disease.
BCL-X1 is a protein which, in healthy cells, is expressed in the outer membranes of the mitochondria, the endoplasmic reticulum, and the nuclear envelope. Its function is to bind to specific protein/protease complexes and prevent cell apoptosis. Upon internal damage to the cell the protein/protease complexes are released, and cause the process of apoptosis to begin. An over-expression of BCL-X1, often present in cancerous and other diseased cells, results in the blocking of apoptotic signals and allows the cells to proliferate (Cancer 1999, 85, 164-170; and references cited therein). It is believed that by blocking BCL-X1, apoptosis can be induced in diseased cells, and can provide an effective therapy for cancer and other diseases caused by the impairment of the apoptotic process. Based on these findings and the absence of BCL-X1 inhibitors from current cancer therapies, there is a continuing need for compounds which can trigger apoptosis through the inhibition of the BCL family of proteins.
In its principle embodiment the present invention provides a compound of formula (I): 
or a therapeutically acceptable salt thereof wherein
A is selected from the group consisting of phenyl and a five- or six-membered aromatic carbocyclic ring wherein from one to three carbon atoms are replaced by a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein A is substituted through carbon atoms in the ring;
R1 is selected from the group consisting of alkyl, haloalkyl, nitro, and xe2x80x94NR5R6;
R2, and R3 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, alkylsulfanyl, alkynyl, aryl, arylalkoxy, aryloxy, aryloxyalkoxy, arylsulfanyl, arylsulfanylalkoxy, carbonyloxy, cycloalkylalkoxy, cycloalkyloxy, halo, haloalkoxy, haloalkyl, heterocycle, (heterocycle)oxy, hydroxy, nitro, and xe2x80x94N5R6,
R4 is selected from the group consisting of aryl, arylalkenyl, arylalkoxy, cycloalkenyl, cycloalkyl, halo, heterocycle, and (heterocycle)alkoxy;
R5 and R6 are independently selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylsulfanylalkyl, alkylsulfonylalkyl, aryl, arylalkyl, arylalkylsulfanylalkyl, aryloxyalkyl, arylsulfanylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, carboxyalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylcarbonyl, heterocycle, (heterocycle)alkyl, (heterocycle)sulfanylalkyl, hydroxyalkyl, a nitrogen protecting group, and xe2x80x94Nxe2x95x90CR7R8; or
R5 and R6, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of imidazolyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolyl, thiomorpholinyl, and thiomorpholinyl dioxide; and
R7 and R8 are alkyl, or
R7 and R8, together with the carbon atom to which they are attached, form an aryl group; and
R15 is selected from the group consisting of hydrogen, alkyl, and halo.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; and R1-R8 and R15 are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R3 is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; and R1, R2, R4-8, and R15 are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R3 is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R2 is selected from the group consisting of arylsulfanylalkoxy, cycloalkylalkoxy, and cycloalkyloxy; and R1, R4, and R15 are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R3 is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R2 is xe2x80x94NR5R6; and R1, R4, R7, R8, and R15 are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R3 is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R2 is xe2x80x94NR5R6; one of R5 and R6 is selected from the group consisting of alkyl, aryl, arylalkyl, arylalkylsulfanylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, cycloalkylcarbonyl, heterocycle, (heterocycle)alkyl, heterocyclesulfanylalkyl, and xe2x80x94Nxe2x95x90CR7R8; and the other is hydrogen; and R1, R4, R7, R8, and R15 are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R3 is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R2 is xe2x80x94NR5R6; one of R5 and R6 is (cycloalkyl)alkyl and the other is arylsulfanylalkyl; and R1, R4, and R15 are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R3 is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R2 is xe2x80x94NR5R6; one of R5 and R6 is cycloalkyl and the other is hydrogen; and R1, R4 and R15 are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R3 is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R2 is xe2x80x94NR5R6; one of R5 and R6 is (cycloalkyl)alkyl and the other is hydrogen; and R1, R4, and R5 are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R3 is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R2 is xe2x80x94NR5R6; one of R5 and R6 is arylsulfanylalkyl and the other is hydrogen; and R1, R4, and R15 are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R3 is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R2 is xe2x80x94NR5R6; one of R5 and R6 is arylalkylsulfanyl and the other is hydrogen; R4 is selected from the group consisting of arylalkenyl, arylalkoxy, cycloalkenyl, cycloalkyl, and (heterocycle)alkoxy; and R1 and R15 are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R3 is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R2 is xe2x80x94NR5R6; one of R5 and R6 is arylsulfanylalkyl and the other is hydrogen; R4 is aryl; and R1 and R15 are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R3 is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R2 is xe2x80x94NR5R6; one of R5 and R6 is arylsulfanylalkyl and the other is hydrogen; R4 is aryl wherein the aryl is unsubstituted or has one substituent; and R1 and R15 are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R3 is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R2 is xe2x80x94NR5R6; one of R5 and R6 is arylsulfanylalkyl and the other is hydrogen; R4 is aryl wherein the aryl has two substituents; and R1 and R15 are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R3 is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R2 is xe2x80x94NR5R6; one of R5 and R6 is arylsulfanylalkyl and the other is hydrogen; R4 is heterocycle; and R1 and R15 are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R3 is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R2 is xe2x80x94NR5R6; one of R5 and R6 is arylsulfanylalkyl and the other is hydrogen; R4 is heterocycle wherein the heterocycle is unsubstitued or has one substituent; and R1 and R15 are as previously defined.
In another embodiment the present invention provides a compound of formula (I) wherein A is selected from the group consisting of phenyl, pyridinyl, and furyl; R3 is selected from the group consisting of hydrogen, alkenyl, aryl, and heterocycle; R2 is xe2x80x94NR5R6; one of R5 and R6 is arylsulfanylalkyl and the other is hydrogen; R4 is heterocycle wherein the heterocycle has two or three substituents; and R1 and R15 are as previously defined.
In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
In another embodiment, the present invention provides a method of promoting apoptosis in a mammal in recognized need thereof comprising administering to the mammal a therapeutically acceptable amount of a compound of formula (I) or a therapeutically acceptable salt thereof.
Compounds of the present invention comprise substituted N-benzoyl arylsulfonamides which are useful for the treatment of apoptosis-mediated diseases.
As used in the present specification the following terms have the meanings indicated.
The term xe2x80x9calkanoyl,xe2x80x9d as used herein, represents an alkyl group attached to the parent molecular moiety through a carbonyl group. The alkanoyl groups of this invention can be optionally substituted with one or two groups independently selected from the group consisting of hydroxy and xe2x80x94NR5R6, wherein R5 and R6 are as previously defined.
The term xe2x80x9calkanoylalkyl,xe2x80x9d as used herein, represents an alkanoyl group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9calkenyl,xe2x80x9d as used herein, represents a straight or branched chain group of one to twelve carbon atoms derived from a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, represents an alkyl group attached to the parent molecular moiety through an oxygen atom.
The term xe2x80x9calkoxyalkanoyl,xe2x80x9d as used herein, represents an alkoxy group attached to the parent molecular moiety through an alkanoyl group.
The term xe2x80x9calkoxyalkoxy,xe2x80x9d as used herein, represents an alkoxy group attached to the parent molecular moiety through another alkoxy group.
The term xe2x80x9calkoxyalkoxyalkyl,xe2x80x9d as used herein, represents an alkoxyalkoxy group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9calkoxyalkoxycarbonyl,xe2x80x9d as used herein, represents an alkoxyalkoxy group attached to the parent molecular moiety through a carbonyl group.
The term xe2x80x9calkoxyalkyl,xe2x80x9d as used herein, represents an alkoxy group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9calkoxycarbonyl,xe2x80x9d as used herein, represents an alkoxy group attached to the parent molecular moiety through a carbonyl group.
The term xe2x80x9calkoxycarbonylalkyl,xe2x80x9d as used herein, represents an alkoxycarbonyl group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9calkyl,xe2x80x9d as used herein, represents a group of one to twelve carbon atoms derived from a straight or branched chain saturated hydrocarbon.
The term xe2x80x9calkylamino,xe2x80x9d as used herein, represents xe2x80x94N(R14)2, wherein R14 is alkyl.
The term xe2x80x9calkylaminoalkyl,xe2x80x9d as used herein, represents an alkylamino group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9calkylaminocarbonyl,xe2x80x9d as used herein, represents an alkylamino group attached to the parent molecular moiety through a carbonyl group.
The term xe2x80x9calkylaminocarbonylalkyl,xe2x80x9d as used herein, represents an alkylaminocarbonyl group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9calkylidene,xe2x80x9d as used herein, represents an alkyl group attached to the parent molecular moiety through a carbon-carbon double bond.
The term xe2x80x9calkylsulfanyl,xe2x80x9d as used herein, represents an alkyl group attached to the parent molecular moiety through a sulfur atom.
The term xe2x80x9calkylsulfanylalkyl,xe2x80x9d as used herein, represents an alkylsulfanyl group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9calkylsulfonyl,xe2x80x9d as used herein, represents an alkyl group attached to the parent molecular moiety through a sulfonyl group.
The term xe2x80x9calkylsulfonylalkyl,xe2x80x9d as used herein, represents an alkylsulfonyl group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9calkynyl,xe2x80x9d as used herein, represents a straight or branched chain group of one to twelve carbon atoms containing at least one carbon-carbon triple bond.
The term xe2x80x9camino,xe2x80x9d as used herein, represents xe2x80x94NR9R10, wherein R9 and R10 are independently selected from the group consisting of hydrogen, alkanoyl, alkenyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxycarbonyl, alkyl, alkylaminoalkyl, alkylaminocarbonylalkyl, aryl, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylcarbonyl, haloalkanoyl, haloalkyl, (heterocycle)alkyl, heterocyclecarbonyl, hydroxyalkyl, a nitrogen protecting group, xe2x80x94C(NH)NH2, and xe2x80x94C(O)NR5R6, wherein R5 and R6 are as previously defined; wherein the aryl; the aryl part of the arylalkyl; the cycloalkyl; the cycloalkyl part of the (cycloalkyl)alkyl and the cycloalkylcarbonyl; and the heterocycle part of the (heterocycle)alkyl and the heterocyclecarbonyl can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkanoyl, alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and nitro.
The term xe2x80x9caminoalkanoyl,xe2x80x9d as used herein, represents an amino group attached to the parent molecular moiety through an alkanoyl group.
The term xe2x80x9caminoalkyl,xe2x80x9d as used herein, represents an amino group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9caminocarbonyl,xe2x80x9d as used herein, represents an amino group attached to the parent molecular moiety through a carbonyl group.
The term xe2x80x9caminocarbonylalkyl,xe2x80x9d as used herein, represents an aminocarbonyl group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9caminosulfonyl,xe2x80x9d as used herein, represents an amino group attached to the parent molecular moiety through a sulfonyl group.
The term xe2x80x9caryl,xe2x80x9d as used herein, represents a phenyl group or a bicyclic or tricyclic fused ring system wherein one or more of the fused rings is a phenyl group. Bicyclic fused ring systems are exemplified by a phenyl group fused to a cycloalkyl group as defined herein, a cycloalkenyl group as defined herein, or another phenyl group. Tricyclic fused ring systems are exemplified by a bicyclic fused ring system fused to a cycloalkyl group as defined herein, a cycloalkenyl group as defined herein, or another phenyl group. Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. Aryl groups having an unsaturated or partially saturated ring fused to an aromatic ring can be attached through the saturated or the unsaturated part of the group. The aryl groups of this invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkanoyl, alkenyl, alkoxy, alkoxyalkanoyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aminosulfonyl, aryl, aryloxy, arylsulfanyl, carbonyloxy, cyano, halo, haloalkoxy, haloalkyl, heterocycle, (heterocycle)alkyl, heterocyclecarbonylalkenyl, heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, nitro, oxo, and xe2x80x94C(NH)NH2, wherein the aryl; the aryl part of the aryloxy and the arylsulfanyl; the heterocycle; and the heterocycle part of the (heterocycle)alkyl, the heterocyclecarbonylalkenyl, and the heterocyclecarbonylalkyl can be further optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxyalkanoyl, alkoxycarbonyl, alkyl, alkylsulfonyl, aminocarbonyl, aminosulfonyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, nitro, oxo, and xe2x80x94C(NH)NH2. In addition, the heterocycle and the heterocycle part of the (heterocycle)alkyl, the heterocyclecarbonylalkenyl, and the heterocyclecarbonylalkyl can be further optionally substituted with an additional aryl group, wherein the aryl can be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, cyano, halo, hydroxy, and nitro.
The term xe2x80x9carylalkenyl,xe2x80x9d as used herein, represents an aryl group attached to the parent molecular moiety through an alkenyl group.
The term xe2x80x9carylalkoxy,xe2x80x9d as used herein, represents an aryl group attached to the parent molecular moiety through an alkoxy group.
The term xe2x80x9carylalkoxyalkanoyl,xe2x80x9d as used herein, represents an arylalkoxy group attached to the parent molecular moiety through an alkanoyl group.
The term xe2x80x9carylalkoxycarbonyl,xe2x80x9d as used herein, represents an arylalkoxy group attached to the parent molecular moiety through a carbonyl group.
The term xe2x80x9carylalkyl,xe2x80x9d as used herein, represents an alkyl group substituted with at least one aryl group. The alkyl part of the arylalkyl can be optionally substituted with one or two amino groups.
The term xe2x80x9carylalkylsulfanyl,xe2x80x9d as used herein, represents an arylalkyl group attached to the parent molecular moiety through a sulfur atom.
The term xe2x80x9carylalkylsulfanylalkyl,xe2x80x9d as used herein, represents an arylalkylsulfanyl group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9carylalkylsulfonyl,xe2x80x9d as used herein, represents an arylalkyl group attached to the parent molecular moiety through a sulfonyl group.
The term xe2x80x9carylcarbonyl,xe2x80x9d as used herein, represents an aryl group attached to the parent molecular moiety through a carbonyl group.
The term xe2x80x9caryloxy,xe2x80x9d as used herein, represents an aryl group attached to the parent molecular moiety through an oxygen atom.
The term xe2x80x9caryloxyalkoxy,xe2x80x9d as used herein, represents an aryloxy group attached to the parent molecular moiety through an alkoxy group.
The term xe2x80x9caryloxyalkyl,xe2x80x9d as used herein, represents an aryloxy group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9carylsulfanyl,xe2x80x9d as used herein, represents an aryl group attached to the parent molecular moiety through a sulfur atom.
The term xe2x80x9carylsulfanylalkoxy,xe2x80x9d as used herein, represents an arylsulfanyl group attached to the parent molecular moiety through an alkoxy group.
The term xe2x80x9carylsulfanylalkyl,xe2x80x9d as used herein, represents an arylsulfanyl group attached to the parent molecular moiety through an alkyl group. The alkyl part of the arylsulfanylalkyl can be optionally substituted with one or two substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, amino, aminocarbonyl, arylalkoxy, azido, carboxy, cycloalkyl, halo, heterocycle, (heterocycle)alkoxy, (heterocycle)carbonyl, and hydroxy.
The term xe2x80x9carylsulfinyl,xe2x80x9d as used herein, represents an aryl group attached to the parent molecular moiety through a sulfinyl group.
The term xe2x80x9carylsulfinylalkyl,xe2x80x9d as used herein, represents an arylsulfinyl group attached to the parent molecular moiety through an alkyl group. The alkyl part of the arylsulfinylalkyl can be optionally substituted with one or two amino groups.
The term xe2x80x9carylsulfonyl,xe2x80x9d as used herein, represents an aryl group attached to the parent molecular moiety through a sulfonyl group.
The term xe2x80x9carylsulfonylalkyl,xe2x80x9d as used herein, represents an arylsulfonyl group attached to the parent molecular moiety through an alkyl group. The alkyl part of the arylsulfonylalkyl can be optionally substituted with one or two amino groups.
The term xe2x80x9cazido,xe2x80x9d as used herein, represents xe2x80x94N3.
The term xe2x80x9ccarbonyl,xe2x80x9d as used herein, represents xe2x80x94C(O)xe2x80x94.
The term xe2x80x9ccarbonyloxy,xe2x80x9d as used herein, represents an alkanoyl group attached to the parent molecular moiety through an oxygen atom.
The term xe2x80x9ccarboxy,xe2x80x9d as used herein, represents xe2x80x94CO2H.
The term xe2x80x9ccarboxyalkyl,xe2x80x9d as used herein, represents a carboxy group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9ccyano,xe2x80x9d as used herein, represents xe2x80x94CN.
The term xe2x80x9ccyanoalkyl,xe2x80x9d as used herein, represents a cyano group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9ccycloalkenyl,xe2x80x9d as used herein, represents a non-aromatic ring system having three to ten carbon atoms and one to three rings, wherein each five-membered ring has one double bond, each six-membered ring has one or two double bonds, each seven- and eight-membered ring has one to three double bonds, and each nine-to ten-membered ring has one to four double bonds. Examples of cycloalkenyl groups include cyclohexenyl, octahydronaphthalenyl, norbornylenyl, and the like. The cycloalkenyl groups of this invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, aminoalkyl, arylalkoxy, aryloxy, arylsulfanyl, halo, haloalkoxy, haloalkyl, and hydroxy, wherein the aryl part of the arylalkoxy, the aryloxy, and the arylsulfanyl can be further optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, halo, haloalkoxy, haloalkyl, and hydroxy.
The term xe2x80x9ccycloalkenylalkyl,xe2x80x9d as used herein, represents a cycloalkenyl group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9ccycloalkyl,xe2x80x9d as used herein, represents a saturated ring system having three to twelve carbon atoms and one to three rings. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, bicyclo(3.1.1)heptyl, adamantyl, and the like. The cycloalkyl groups of this invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkoxy, alkoxycarbonyl, alkyl, aminoalkyl, arylalkoxy, aryloxy, arylsulfanyl, halo, haloalkoxy, haloalkyl, and hydroxy, wherein the aryl part of the arylalkoxy, the aryloxy, and the arylsulfanyl can be further optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkyl, halo, haloalkoxy, haloalkyl, and hydroxy.
The term xe2x80x9ccycloalkylalkoxy,xe2x80x9d as used herein, represents a cycloalkyl group attached to the parent molecular moiety through an alkoxy group.
The term xe2x80x9c(cycloalkyl)alkyl,xe2x80x9d as used herein, represents a cycloalkyl group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9ccycloalkylcarbonyl,xe2x80x9d as used herein, represents a cycloalkyl group attached to the parent molecular moiety through a carbonyl group.
The term xe2x80x9ccycloalkyloxy,xe2x80x9d as used herein, represents a cycloalkyl group attached to the parent molecular moiety through an oxygen atom.
The term xe2x80x9cformyl,xe2x80x9d as used herein, represents xe2x80x94CHO.
The term xe2x80x9cformylalkyl,xe2x80x9d as used herein, represents a formyl group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9chalo,xe2x80x9d as used herein, represents F, Cl, Br, or I.
The term xe2x80x9chaloalkanoyl,xe2x80x9d as used herein, represents a haloalkyl group attached to the parent molecular moiety through a carbonyl group.
The term xe2x80x9chaloalkoxy,xe2x80x9d as used herein, represents a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
The term xe2x80x9chaloalkyl,xe2x80x9d as used herein, represents an alkyl group substituted by one, two, three, or four halogen atoms.
The term xe2x80x9cheteroalkenylene,xe2x80x9d as used herein, represents a divalent group of three to eight atoms derived from a straight or branched chain containing at least one carbon-carbon double bond that contains one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the remaining atoms are carbon. The heteroalkenylene groups of the present invention can be attached to the parent molecular moiety through the carbon atoms or the heteroatoms in the chain.
The term xe2x80x9cheteroalkylene,xe2x80x9d as used herein, represents a divalent group of two to eight atoms derived from a saturated straight or branched chain containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, wherein the remaining atoms are carbon. The heteroalkylene groups of the present invention can be attached to the parent molecular moiety through the carbon atoms or the heteroatoms in the chain.
The term xe2x80x9cheterocycle,xe2x80x9d as used herein, represents a monocyclic, bicyclic, or tricyclic ring system wherein one or more rings is a four-, five-, six-, or seven-membered ring containing one, two, or three heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Monocyclic ring systems are exemplified by any 3- or 4-membered ring containing a heteroatom independently selected from the group consisting of oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from the group consisting of nitrogen, oxygen and sulfur. The 3- and 4-membered rings have no double bonds, the 5-membered ring has from 0-2 double bonds and the 6- and 7-membered rings have from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole, trithiane, and the like. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, a cycloalkenyl group, as defined herein, or another monocyclic heterocycle ring system. Representative examples of bicyclic ring system include but are not limited to, benzimidazole, benzothiazole, benzothiophene, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and the like. Tricyclic rings systems are exemplified by any of the above bicyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, a cycloalkenyl group as defined herein, or another monocyclic heterocycle ring system. Representative examples of tricyclic ring systems include, but are not limited to, acridine, carbazole, carboline, dibenzofuran, dibenzothiophene, naphthofuran, naphthothiophene, oxanthrene, phenazine, phenoxathiin, phenoxazine, phenothiazine, thianthrene, thioxanthene, xanthene, and the like. Heterocycle groups can be attached to the parent molecular moiety through a carbon atom or a nitrogen atom in the group.
The heterocycle groups of the present invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkanoyl, alkanoylalkyl, alkenyl, alkoxy, alkoxyalkoxycarbonyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylsulfanylalkyl, alkynyl, amino, aminoalkanoyl, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aminosulfonyl, aryl, arylalkoxyalkanoyl, arylalkoxycarbonyl, arylalkyl, arylalkylsulfonyl, arylcarbonyl, aryloxy, arylsulfanyl, arylsulfanylalkyl, arylsulfonyl, carbonyloxy, carboxy, cyano, cyanoalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylcarbonyl, formyl, formylalkyl, halo, haloalkoxy, haloalkyl, heterocycle, (heterocycle)alkyl, (heterocycle)alkylidene, heterocyclecarbonyl, heterocyclecarbonylalkyl, hydroxy, hydroxyalkyl, nitro, oxo, spirocycle, spiroheterocycle, and xe2x80x94C(NH)NH2; wherein the aryl; the aryl part of the arylalkylsulfonyl, the arylcarbonyl, the aryloxy, the arylalkoxyalkanoyl, the arylalkoxycarbonyl, the arylalkyl, the arylsulfanyl, the arylsulfanylalkyl, and the arylsulfonyl; the heterocycle; and the heterocycle part of the (heterocycle)alkyl, the (heterocycle)alkylidene, the heterocyclecarbonyl, and the heterocyclecarbonylalkyl can be further optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkanoyl, alkoxy, alkoxyalkoxycarbonyl, alkoxycarbonyl, alkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and nitro.
The term xe2x80x9c(heterocycle)alkoxy,xe2x80x9d as used herein, represents a heterocycle group attached to the parent molecular moiety through an alkoxy group.
The term xe2x80x9c(heterocycle)alkyl,xe2x80x9d as used herein, represents a heterocycle group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9c(heterocycle)alkylidene,xe2x80x9d as used herein, represents a heterocycle group attached to the parent molecular moiety through an alkylidene group.
The term xe2x80x9cheterocyclecarbonyl,xe2x80x9d as used herein, represents a heterocycle group attached to the parent molecular moiety through a carbonyl group.
The term xe2x80x9cheterocyclecarbonylalkenyl,xe2x80x9d as used herein, represents a heterocyclecarbonyl group attached to the parent molecular moiety through an alkenyl group.
The term xe2x80x9cheterocyclecarbonylalkyl,xe2x80x9d as used herein, represents a heterocyclecarbonyl group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9c(heterocycle)oxy,xe2x80x9d as used herein, represents a heterocycle group attached to the parent molecular moiety through an oxygen atom.
The term xe2x80x9c(heterocycle)sulfanyl,xe2x80x9d as used herein, represents a heterocycle group attached to the parent molecular moiety through a sulfur atom.
The term xe2x80x9c(heterocycle)sulfanylalkyl,xe2x80x9d as used herein, represents a heterocyclesulfanyl group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9chydroxy,xe2x80x9d as used herein, represents xe2x80x94OH.
The term xe2x80x9chydroxyalkyl,xe2x80x9d as used herein, represents a hydroxy group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9cnitro,xe2x80x9d as used herein, represents xe2x80x94NO2.
The term xe2x80x9cnitrogen protecting group,xe2x80x9d as used herein, represents groups intended to protect an amino group against undesirable reactions during synthetic procedures. Common N-protecting groups comprise acyl groups such as acetyl, benzoyl, 2-bromoacetyl, 4-bromobenzoyl, tert-butylacetyl, carboxaldehyde, 2-chloroacetyl, 4-chlorobenzoyl, a-chlorobutyryl, 4-nitrobenzoyl, o-nitrophenoxyacetyl, phthalyl, pivaloyl, propionyl, trichloroacetyl, and trifluoroacetyl; sulfonyl groups such as benzenesulfonyl, and p-toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl, benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, and the like.
The term xe2x80x9coxo,xe2x80x9d as used herein, represents (xe2x95x90O).
The term xe2x80x9cspirocycle,xe2x80x9d as used herein, represents an alkyl diradical of two to eight atoms, each end of which is attached to the same carbon atom of the parent molecular moiety.
The term xe2x80x9cspiroheterocycle,xe2x80x9d as used herein, represents a heteroalkylene diradical, each end of which is attached to the same carbon atom of the parent molecular moiety. Examples of spiroheterocycles include dioxolanyl, tetrahydrofuranyl, pyrrolidinyl, and the like.
The term xe2x80x9csulfinyl,xe2x80x9d as used herein, represents xe2x80x94S(O)xe2x80x94.
The term xe2x80x9csulfonyl,xe2x80x9d as used herein, represents xe2x80x94SO2xe2x80x94.
The term xe2x80x9ctherapeutically acceptable salt,xe2x80x9d as use herein, represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the present invention or separately by reacting a free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, trifluoroacetate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include calcium, lithium, magnesium, potassium, sodium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, dimethylamine, ethylamine, methylamine, tetraethylammonium, tetramethylammonium, triethylamine, trimethylamine, and the like.
Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,Nxe2x80x2-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
The present compounds can also exist as therapeutically acceptable prodrugs. The term xe2x80x9ctherapeutically acceptable prodrug,xe2x80x9d refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. The term xe2x80x9cprodrug,xe2x80x9d refers to compounds which are rapidly transformed in vivo to parent compounds of formula (I) for example, by hydrolysis in blood.
Asymmetric centers exist in the compounds of the present invention. These centers are designated by the symbols xe2x80x9cRxe2x80x9d or xe2x80x9cS,xe2x80x9d depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, or mixtures thereof, which possess the bility to induce apoptosis. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
According to methods of treatment, the compounds of the present invention can be useful for the prevention of metastases from the tumors described above either when used alone or in combination with radiotherapy and/or other chemotherapeutic treatments conventionally administered to patients for treating cancer. When using the compounds of the present invention for chemotherapy, the specific therapeutically effective dose level for any particular patient will depend upon factors such as the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the compound employed; the duration of treatment; and drugs used in combination with or coincidently with the compound used. For example, when used in the treatment of solid tumors, compounds of the present invention can be administered with chemotherapeutic agents such as alpha inteferon, COMP (cyclophosphamide, vincristine, methotrexate, and prednisone), etoposide, mBACOD (methortrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone), PRO-MACE/MOPP (prednisone, methotrexate (w/leucovin rescue), doxorubicin, cyclophosphamide, taxol, etoposide/mechlorethamine, vincristine, prednisone, and procarbazine), vincristine, vinblastine, angioinhibins, TNP-470, pentosan polysulfate, platelet factor 4, angiostatin, LM-609, SU-101, CM-101, Techgalan, thalidomide, SP-PG, and the like. For example, a tumor may be treated conventionally with surgery, radiation or chemotherapy and a compound of the present invention subsequently administered to extend the dormancy of micrometastases and to stabilize and inhibit the growth of any residual primary tumor.
The compounds of the present invention can be administered orally, parenterally, osmotically (nasal sprays), rectally, vaginally, or topically in unit dosage formulations containing carriers, adjuvants, diluents, vehicles, or combinations thereof. The term xe2x80x9cparenteralxe2x80x9d includes infusion as well as subcutaneous, intravenous, intramuscular, and intrasternal injection.
Parenterally administered aqueous or oleaginous suspensions of the compounds of the present invention can be formulated with dispersing, wetting, or suspending agents. The injectable preparation can also be an injectable solution or suspension in a diluent or solvent. Among the acceptable diluents or solvents employed are water, saline, Ringer""s solution, buffers, dilute acids or bases, dilute amino acid solutions, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as monoglycerides or diglycerides.
The chemotherapeutic effect of parenterally administered compounds can be prolonged by slowing their absorption. One way to slow the absorption of a particular compound is administering injectable depot forms comprising suspensions of crystalline, amorphous, or otherwise water-insoluble forms of the compound. The rate of absorption of the compound is dependent on its rate of dissolution which is, in turn, dependent on its physical state. Another way to slow absorption of a particular compound is administering injectable depot forms comprising the compound as an oleaginous solution or suspension. Yet another way to slow absorption of a particular compound is administering injectable depot forms comprising microcapsule matrices of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides. Depending on the ratio of drug to polymer and the composition of the polymer, the rate of drug release can be controlled.
Transdermal patches also provide controlled delivery of the compounds. The rate of absorption can be slowed by using rate controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound can optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or microcrystalline cellulose. Capsules, tablets and pills can also comprise buffering agents; and tablets and pills can be prepared with enteric coatings or other release-controlling coatings. Powders and sprays can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons or substitutes thereof
Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs comprising inert diluents such as water. These compositions can also comprise adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents.
Topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and transdermal patches. The compound is mixed under sterile conditions with a carrier and any needed preservatives or buffers. These dosage forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Suppositories for rectal or vaginal administration can be prepared by mixing the compounds of the present invention with a suitable nonirritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina. Ophthalmic formulations comprising eye drops, eye ointments, powders, and solutions are also contemplated as being within the scope of the present invention.
The total daily dose of the compounds of the present invention administered to a host in single or divided doses can be in amounts from about 0.1 to about 200 mg/kg body weight or preferably from about 0.25 to about 100 mg/kg body weight. Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose.
Assays for the inhibition of BCL-X1 were performed in 96-well microtiter plates. Compounds of the present invention were diluted in DMSO to concentrations between 100 xcexcM and 1 pM and introduced into each cell of the plate. A mixture totaling 125 xcexcL per well of assay buffer (20 mM phosphate buffer (pH 7.4), 1 mM EDTA, 0.05% PEG-8000), 50 nM of BCL-X1 protein (prepared according to the procedure described in Science 1997, 275, 983-986), 5 nM fluorescein-labeled BAD peptide (purchased from Synpep, Calif.), and the DMSO solution of the compound of the present invention was shaken for 2 minutes and placed in a LJL Analyst (LJL Bio Systems, Calif.). A negative control (DMSO, 5 nM BAD peptide, assay buffer) and a positive control (DMSO, 5 nM BAD peptide, 50 nM BCL-X1, assay buffer) were used to determine the range of the assay. Polarization was measured at room temperature using a continuous Fluorescein lamp (excitation 485 mM, emission 530 mM). Percentage of inhibition was determined by (1-((mP value of well-negative control)/range))xc3x97100%. IC50 values were calculated using Microsoft Excel. Compounds of the present invention have IC50 values between 0.011 and 10 xcexcM and are therefore useful for inhibiting BCL-X1 and treating apoptosis-mediated diseases. Preferred compounds of the present invention have IC50 values between 0.011 and 0.5 xcexcM, and most preferred compounds have IC50 values between 0.011 and 0.10 xcexcM.
Assays for the inhibition of BCL-2 were performed in 96-well microtiter plates. Compounds of the instant invention were diluted in DMSO to concentrations between 100 xcexcM and 1 pM and introduced into each well of the plate. A mixture totaling 125 xcexcL per well of assay buffer (20 mM phosphate buffer (pH 7.4), 1 mM EDTA, 0.05% PF-68), 30 nM of BCL-2 protein (prepared according to the procedure described in PNAS 2001, 98, 3012-3017), 5 nM fluorescein-labeled BAX peptide (prepared in-house), and the DMSO solution of the compound of the instant invention was shaken for 2 minutes and placed in a LJL Analyst (LJL Bio Systems, Calif.). A negative control (DMSO, 5 nM BAX peptide, assay buffer) and a positive control (DMSO, 5 nM BAX peptide, 30 nM BCL-2, assay buffer) were used to determine the range of the assay. Polarization was measured at room temperature using a continuous Fluorescein lamp (excitation 485 mM, emission 530 mM). Percentage of inhibition was determined by (1-((mP value of well-negative control)/range))xc3x97100%. IC50 values were calculated using Microsoft Excel. Compounds of the present invention have IC50 values between 0.017 and 10 xcexcM and are therefore useful for inhibiting BCL-2 and treating apoptosis-mediated diseases. Preferred compounds of the present invention have IC50 values between 0.017 and 0.5 xcexcM, and most preferred compounds have IC50 values between 0.017 and 0.20 xcexcM.
Based upon the structural and functional similarity of the BCL antiapoptotic proteins, it is reasonable to expect that in addition to inducing apoptosis by the inhibition of BCL-X1 and BCL-2, the current invention may induce apoptosis through their action on other antiapoptotic proteins in the Bcl family of proteins, such as BCL-w, BCL-b, MCL-1 and/or A1/Bfl-1.
Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: OAc for acetate; CyMAP-1 for 2-dicyclohexylphosphino-2xe2x80x2-(N,N-dimethylamino)biphenyl; dba for dibenzylideneacetone; dppf for diphenylphosphinoferrocene; DMF for N,N-dimethylformamide; DME for 1,2-dimethoxyethane; THF for tetrahydrofuran; MTBE for methyl tert-butyl ether; NMP for N-methylpyrroldinone; TFP for tris-2-furylphosphine; EDCI for 1-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride; DMAP for 4-dimethylaminopyridine; DCC for 1,3-dicyclohexylcarbodiimide; CDI for 1,1xe2x80x2-carbonyldiimidazole; DMSO for dimethylsulfoxide; TFA for trifluoroacetic acid; NaHMDS for sodium hexamethyldisilazide; LAH for lithium aluminum hydride; p-TsOH for p-toluenesulfonic acid; DIBAL-H for diisobutylaluminum hydride; Fmoc for 9-fluorenylmethyl carbamate; Asp(OtBu)xe2x80x94OH for aspartic acid (4-tert-butyl ester); Lys(BOC)xe2x80x94OH for Nxcex5-tert-butyoxycarbonyl lysine; HOBT for 1-hydroxybenzotriazole; BOC for tert-butoxycarbonyl; DEAD for diethyl azodicarboxylate; TBAF for tetrabutylammonium fluoride; BINAP for 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl; Boc-Ser-OMe for N-tert-butoxycarbonyl serine methyl ester; DMA for N,N-dimethylacetamide; and HMPA for hexamethylphosphoramide.
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared. The groups R1, R2, R3, and R4 are as defined above unless otherwise noted below. It will be readily apparent to one of ordinary skill in the art that the compounds defined above can be synthesized by substitution of the appropriate reactants and agents in the syntheses shown below. It will also be apparent that protection and deprotection steps, as well as the order of the steps themselves, can be carried out in varying order to successfully complete the syntheses of compounds of the present invention.
This invention is intended to encompass compounds of formula (I) when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro. 
As shown in Scheme 1, compounds of formula (1) (Ar is aryl or heterocycle; X is halo; R11 is alkyl) can be reacted with compounds of formula (2) (R4 is an unsaturated group such as aryl or alkenyl; R12 is hydrogen or alkyl) in the presence of catalytic palladium and base to provide compounds of formula (3). Examples of palladium catalysts include Pd(PPh3)4, Pd(OAc)2/CyMAP-1, and Pd2(dba)3/AsPh3, and Pd(dppf)Cl2.CH2Cl2. Representative bases include Na2CO3, CsF, and Cs2CO3. Examples of solvents used in these reactions include toluene, dioxane, DMF, ethanol, DME, and mixtures thereof The reaction temperature is about 75xc2x0 C. to about 120xc2x0 C. and depends on the method chosen. Reaction times are typically about 1 to about 24 hours.
Compounds of formula (3) (R11 is alkyl) can be hydrolyzed in the presence of aqueous base to form compounds of formula (3) (R11 is hydrogen). Examples of bases include LiOH, NaOH, and KOH. Representative solvents include water, THF, dioxane, and mixtures thereof. The reaction temperature is about 25xc2x0 C. to about 60xc2x0 C. and depends on the method chosen. Reaction times are typically about 1 to about 18 hours. 
An alternative synthesis of compounds of formula (3) is shown in Scheme 2. Compounds of formula (4) (Ar is optionally substituted aryl or optionally substituted heterocycle; R11 is hydrogen or alkyl; R12 is hydrogen or alkyl) can be reacted with compounds of formula (5) (R4 is previously defined; X is halo or triflate) using the conditions described in Scheme 1 to provide compounds of formula (3). 
As shown in Scheme 3, compounds of formula (6) (X is F or Cl) can be converted to compounds of formula (7) by treatment with ammonium hydroxide. Examples of solvents used in this reaction include diethyl ether, THF, and MTBE. The reaction temperature is about xe2x88x925xc2x0 C. to about 25xc2x0 C. and reaction times are typically about 15 minutes to about 1 hour. In a preferred embodiment, compounds of formula (6) in diethyl ether at 0xc2x0 C. are treated with concentrated ammonium hydroxide and stirred for 30 minutes to provide compounds of formula (7).
The method chosen for the conversion of compounds of formula (7) to compounds of formula (8) is dependent on R2. Compounds of formula (8) wherein R2 is xe2x80x94NR5R6 can be formed by treating compounds of formula (7) with the appropriately substituted amine. Examples of solvents used in this reactions include DMF, dioxane, and NMP. Reaction temperatures are about 35xc2x0 C. to about 130xc2x0 C. and reaction times are typically about 8 to about 24 hours. Compounds of formula (8) wherein R2 is alkoxy, alkylsulfanyl, aryloxy, arylsulfanyl, cycloalkylalkoxy, cycloalkyloxy, (heterocycle)oxy, or perfluoroalkoxy can be formed by treating compounds of formula (7) with the appropriately substituted alcohol in the presence of base. Representative bases include NaH/15-crown-5, and NaH, KH/18-crown-6. Examples of solvents used in this reaction include DMF, THF, NMP, and dioxane. The reaction temperature is about 20xc2x0 C. to about 120xc2x0 C. and the reaction times are typically about 30 minutes to about 24 hours. 
As shown in Scheme 4, compounds of formula (8) can be reacted with 1,3-dibromo-5,5-dimethylhydantoin (9) in the presence of trifluoracetic acid to provide compounds of formula (10). Examples of solvents used in this reaction include dichloromethane, 1,2-dichloroethane, and chloroform. The reaction temperature is about 20xc2x0 C. to about 35xc2x0 C., and the reaction time is typically about 6 to about 24 hours. In a preferred embodiment, compounds of formula (8) in dichloromethane at room temperature are treated with 1,3-dibromo-5,5-dimethylhydantoin (9) and stirred for 18 hours to provide compounds of formula (10).
Compounds of formula (10) can be converted to compounds of formula (12) by coupling with compounds of formula (11) (M is SnBu3 or B(OR13)2) in the presence of a palladium catalyst. Representative palladium catalysts include Pd(PPh3)4, Pd(dppf)Cl2.CH2Cl2, and Pd2(dba)3/TFP. Examples of solvents include acetonitrile, dioxane, and DMF. The reaction temperature is about 35xc2x0 C. to about 110xc2x0 C. and depends on the method chosen. Reaction times are typically about 8 to about 48 hours. 
As shown in Scheme 5, compounds of formula (3) (R11 is hydrogen) can be reacted with compounds of formula (13) in the presence of an activating agent to provide compounds of formula (14). Representative activating agents include EDCI/DMAP, DCC/DMAP, and CDI/DMAP. Examples of solvents used in these reactions include dichloromethane, chloroform, and DMF. The reaction temperature is about 20xc2x0 C. to about 40xc2x0 C. and depends on the method chosen. Reaction times are typically about 8 to about 24 hours. 
Scheme 6 shows the synthesis of compounds of formula (18) (a is 0-5 and each R16 is a heterocycle substituent). Compounds of formula (14) (R11 is alkyl) can be reacted with compounds of formula (15) in the presence of acetyl chloride to provide compounds of formula (16). Examples of solvents used in these reactions include 1,2-dichloroethane, chloroform, and carbon tetrachloride. The reaction is conducted at about 80 to about 90xc2x0 C. for about 1 to about 6 hours.
Conversion of compounds of formula (16) to compounds of formula (17) can be accomplished by treatment with a reducing agent. Representative reducing agents include BF3xe2x80x94Et2O/NaBH4 and B2H6. Examples of solvents used in these reactions include diethyl ether, THF, toluene, and dichloromethane. The reaction is conducted at about 0xc2x0 C. to about 100xc2x0 C. and reaction times are typically about 1 to about 12 hours.
Compounds of formula (17) can be converted to compounds of formula (18) following the methods described in Scheme 5.
The present invention will now be described in connection with certain preferred embodiments which are not intended to limit its scope. On the contrary, the present invention covers all alternatives, modifications, and equivalents as can be included within the scope of the claims. Thus, the following examples, which include preferred embodiments, will illustrate the preferred practice of the present invention, it being understood that the examples are for the purposes of illustration of certain preferred embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.
Compounds of the invention were named by ACD/ChemSketch version 4.5 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or were given names which appeared to be consistent with ACD nomenclature.